Early life arsenic exposure and adult mortality in Region II, Chile Millions of people in the US and worldwide are exposed to high concentrations of arsenic in their drinking water, and the estimated risks of cancer, cardiovascular disease, and other adverse outcomes associated with these exposures is very high. From 1958 to 1970, over 125,000 people in the city of Antofagasta in Region II of Chile experienced a sudden and unusual period of high drinking water arsenic concentrations. This exposure period was highly distinct, with low exposure before the highly contaminated drinking water sources were first used in 1958, and a sudden drop in water arsenic concentrations (from around 870 5g/L to eventually 10 5g/L) when an arsenic removal plant was installed in 1971. As far as we know, a scenario like this, in such a large and uniformly exposed population, has never been reported for any environmental contaminant. Our investigation of this unique population has already been highly productive. For example, we identified major increases in mortality in Antofagasta among people who were young children or in utero during the high exposure period. These increases were found for bladder cancer (standardized mortality ratio [SMR]=21.3;95% confidence interval [CI], 11.6 to 35.7), laryngeal cancer (SMR=10.5;95% CI, 3.4 to 24.6), lung cancer (SMR=6.8;95% CI, 5.4 to 8.4), kidney cancer (SMR=3.4;95% CI, 1.7 to 6.2) and liver cancer (SMR=3.1;95% CI, 1.8 to 4.9). Non-cancer deaths were increased from bronchiectasis (SMR=25.1;95% CI, 13.4 to 42.9), acute myocardial infarction (SMR=2.4;95% CI, 1.9 to 3.0) and chronic renal disease (SMR=2.3;95% CI, 1.6 to 3.3). Increases were greatest for those born during the high exposure period (with likely in utero exposure) for bladder cancer (SMR=55.9;95%CI, 25.5 to 106) and bronchiectasis (SMR=46.2;95%CI, 21.1 to 87.7). This was the first human study to link early life exposure to a common drinking water contaminant to high risks of cancer and non-cancer outcomes in adults. Because of the timing of the high exposure period (1958-1970), our previous studies could only assess the long-term effects of early life exposure in relatively young adults (i.e., those in their 30s and 40s). In this proposal, we seek to extend our investigation to cover ten additional years of mortality data, from 2001-2010. This will allow us to evaluate whether the effects of early life exposure we identified in young adults continue into older age groups. This is important because the baseline risks for most chronic diseases are higher in these older age groups. Because of these higher baseline risks, increases in relative risk due to arsenic in these older groups would cause larger numbers of arsenic-related deaths, and therefore larger increases in the overall burden of disease in exposed populations. Currently, many people in the US use private wells with high concentrations of arsenic, including some as high or higher than they were in Antofagasta. Region II of Chile provides the best population in the world to assess the effects of early life arsenic exposure. The reasons include the fact that this is the driest inhabited place on earth, with only one water source for each town and city and accurate records of arsenic concentrations for the last 50 years or more. The limited number of water sources and availability of good records means that arsenic exposure from the distant past can be assessed with greater accuracy than can be done anywhere else in the world. This accurate data on exposure substantially reduces the exposure assessment problems (i.e., ecologic fallacy) commonly seen in many ecologic studies. Another advantage is that the number of people who were highly exposed in Antofagasta is more than ten times greater than in any other published arsenic study in the world. In this situation, the ecologic study design is ideal, since it allows us to study a variety of different causes of death, in a very large exposed population, with good data on past exposure, good statistical power, and a low probability of major confounding. This mortality study is probably the only opportunity available to see if the already identified major effects of early life exposure to arsenic on multiple causes of death in young adults continues into older age groups. This would have several important public health implications. For example, health care providers in the US and worldwide would need to be more alert to arsenic health effects and exposure, especially in pregnant women, infants, and young children, and should ask all patients from rural areas if they have private wells, and if they have been tested for arsenic. In addition, the current drinking water standard of 10 5g/L might need further examination, since the risk estimates on which this standard is based did not consider the risks associated with early life exposure. PUBLIC HEALTH RELEVANCE: Arsenic exposure from drinking water is a widespread health hazard throughout the world, including the United States where millions of people drink water from private wells which are quite often contaminated with arsenic. We have shown so far in our mortality study in Chile, the exposure of mothers during pregnancy, and of their children, results in major increase in mortality in young adults. Since this is the highest known risk after any early life exposure, we think it is critically important to continue this mortality study a further ten years to more fully ascertain the magnitude of the long term effects.